The mechanisms underlying neuropathic pain states are not completely understood, and therapeutic options are less than satisfactory. Clinical and experimental studies conducted by our group indicate that opioids attenuate neuropathic pain. The use of systemic opioids for pain, however, is limited by their central nervous system side effects, e.g., sedation and cognitive dysfunction. Recent reports and preliminary studies by our group indicate that peripheral u-opioid receptor (MOR) mediated mechanisms may play a role in opioid analgesia in neuropathic pain. Using L5 spinal nerve ligation in rodents as a model of neuropathic pain, studies are proposed to characterize peripheral MOR-mediated analgesia, examine its mechanisms, and determine if enhancing peripheral MOR-mediated analgesia will lead to a decrease in systemic or intrathecal opioid requirements. Specific Aim 1 will determine if the site of action for the antihyperalgesic effects of peripherally acting MOR agonists in neuropathic pain is near cutaneous terminals of primary afferentsor at other sites along the nerve or dorsal root ganglia (DRG). Behavioral studies will be performed in neuropathic animals before and after systemic and intraplantar administration of the peripherally acting MOR agonist, loperamide. Specific Aim 2 will use immuno-histochemical and molecular biological strategies to determine if MOR expression in primary afferent neurons is altered after L5 spinal nerve injury. We postulate that L5 spinal nerve injury results in compensatory upregulation of MOR in the L4 DRG and increased transport of MORs to the periphery. Specific aim 3 will use neurophysiologic techniques to determine the mechanisms underlying the effects of peripherally acting MOR agonists in neuropathic pain. The effects of peripheral opioids on the response properties of primary afferent nociceptors and the maintenance of central sensitization of spinal dorsal horn cells after nerve injury will be studied. Specific Aim 4 will examine if overexpression of MORs in primary afferents by topical administration of recombinant herpes simplex viral vectors can be used as a strategy for the treatment of neuropathic pain. We will investigate if increasing the MOR expression on primary afferents will lead to a leftward shift in the analgesic dose-response curves of peripheral, intrathecal, and systemic opioid agonists. The proposed studies should provide new insights into the mechanisms of the peripheral antihyperalgesic effects of opioids on neuropathic pain and should lead to novel therapeutic strategies.